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The combination of olaratumab with gemcitabine and docetaxel arrests a chemotherapy-resistant undifferentiated soft-tissue sarcoma in a patient-derived orthotopic xenograft mouse model

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Abstract

Purpose

Olaratumab (OLA) is a monoclonal antibody against platelet-derived growth factor receptor alpha. OLA has recently been used against soft-tissue sarcoma (STS) combined with doxorubicin (DOX), but with limited efficacy. The goal of present study was to determine the efficacy of OLA combined with gemcitabine (GEM) and docetaxel (DOC) on a chemotherapy-resistant STS patient-derived orthotopic xenograft (PDOX).

Methods

Undifferentiated soft-tissue sarcoma (USTS) from a striated muscle of a patient was grown orthotopically in the right biceps femoris muscle of nude mice to establish the PDOX model. The USTS PDOX was treated with GEM alone, GEM combined with DOC, OLA combined with DOX or GEM, and OLA combined with GEM and DOC. Tumor size and body weight were measured during the 14 days of treatment.

Results

Tumor growth was arrested only by OLA combined with GEM and DOC. Tumors treated with OLA combined with GEM and DOC also had the most necrosis.

Conclusions

The present study demonstrates the power of the PDOX model to identify the novel effective treatment strategy of the combination of OLA, GEM and DOC for drug-resistant soft-tissue sarcoma.

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References

  1. Fletcher CD (2008) Undifferentiated sarcomas: what to do? And does it matter? A surgical pathology perspective. Ultrastruct Pathol 32(2):31–36

    Article  Google Scholar 

  2. American Cancer Society (2019) Cancer facts and figs. American Cancer Society, Atlanta

    Google Scholar 

  3. Doyle LA (2014) Sarcoma classification: an update based on the 2013 World Health Organization Classification of tumors of soft tissue and bone. Cancer 120:1763–1774

    Article  Google Scholar 

  4. Antoniou G, Lee ATJ, Huang PH, Jones RL (2018) Olaratumab in soft tissue sarcoma—current status and future perspectives. Eur J Cancer 92:33–39

    Article  CAS  Google Scholar 

  5. Demoulin JB, Essaghir A (2014) PDGF receptor signaling networks in normal and cancer cells. Cytokine Growth Factor Rev 25(3):273–283

    Article  CAS  Google Scholar 

  6. Doi T, Ma Y, Dontabhaktuni A, Nippgen C, Nippgen J, Ohtsu A (2014) Phase I study of olaratumab in Japanese patients with advanced solid tumors. Cancer Sci 105(7):862–869

    Article  CAS  Google Scholar 

  7. Ehnman M, Missiaglia E, Folestad E, Selfe J, Strell C, Thway K, Brodin B, Pietras K, Shipley J, Östman A, Eriksson U (2013) Distinct effects of ligand-induced PDGFRalpha and PDGFRbeta signaling in the human rhabdomyosarcoma tumor cell and stroma cell compartments. Cancer Res 73(7):2139–2149

    Article  CAS  Google Scholar 

  8. Tap WD, Jones RL, Van Tine BA, Chmielowski B, Elias AD, Adkins D, Agulnik M, Cooney MM, Livingston MB, Pennock G, Hameed MR, Shah GD, Qin A, Shahir A, Cronier DM, Ilaria R Jr, Conti I, Cosaert J, Schwartz GK (2016) Olaratumab and doxorubicin versus doxorubicin alone for treatment of soft-tissue sarcoma: an open-label phase 1b and randomised phase 2 trial. Lancet 388(10043):488–497

    Article  CAS  Google Scholar 

  9. Seddon B, Strauss SJ, Whelan J, Leahy M, Woll PJ, Cowie F, Rothermundt C, Wood Z, Benson C, Ali N, Marples M, Veal GJ, Jamieson D, Küver K, Tirabosco R, Forsyth S, Nash S, Dehbi HM, Beare S (2017) Gemcitabine and docetaxel versus doxorubicin as first-line treatment in previously untreated advanced unresectable or metastatic soft-tissue sarcomas (GeDDiS): a randomised controlled phase 3 trial. Lancet Oncol 18(10):1397–1410

    Article  CAS  Google Scholar 

  10. Villalobos VM, Redondo A, Tine BAV, Schwartz GK, Dickson MA, Chmielowski B, Peterson P, Cronier D, Wright JA, Attia S (2018) Phase 1b/2 study of olaratumab plus gemcitabine and docetaxel for the treatment of advanced soft tissue sarcoma (STS) (ANNOUNCE 2): phase 1b results. J Clin Oncol 36(15_suppl):11542

    Article  Google Scholar 

  11. Igarashi K, Kawaguchi K, Li S, Han Q, Tan Y, Murakami T, Kiyuna T, Miyake K, Miyake M, Singh AS, Eckardt MA, Nelson SD, Russell TA, Dry SM, Li Y, Yamamoto N, Hayashi K, Kimura H, Miwa S, Tsuchiya H, Singh SR, Eilber FC, Hoffman RM (2018) Recombinant methioninase in combination with doxorubicin (DOX) overcomes first-line DOX resistance in a patient-derived orthotopic xenograft nude-mouse model of undifferentiated spindle-cell sarcoma. Cancer Lett 417:168–173

    Article  CAS  Google Scholar 

  12. Kiyuna T, Tome Y, Murakami T, Kawaguchi K, Igarashi K, Miyake K, Miyake M, Li Y, Nelson SD, Dry SM, Singh AS, Russell TA, Elliott I, Singh SR, Kanaya F, Eilber FC, Hoffman RM (2018) Trabectedin arrests a doxorubicin-resistant PDGFRA-activated liposarcoma patient-derived orthotopic xenograft (PDOX) nude mouse model. BMC Cancer 18(1):840

    Article  Google Scholar 

  13. Higuchi T, Kawaguchi K, Miyake K, Oshiro H, Zhang Z, Razmjooei S, Wangsiricharoen S, Igarashi K, Yamamoto N, Hayashi K, Kimura H, Miwa S, Nelson SD, Dry SM, Li Y, Chawla SP, Eilber FC, Singh SR, Tsuchiya H, Hoffman RM (2019) The combination of gemcitabine and nab-paclitaxel as a novel effective treatment strategy for undifferentiated soft-tissue sarcoma in a patient-derived orthotopic xenograft (PDOX) nude-mouse model. Biomed Pharmacother 111:835–840

    Article  CAS  Google Scholar 

  14. Igarashi K, Kawaguchi K, Kiyuna T, Miyake K, Miyake M, Singh AS, Eckardt MA, Nelson SD, Russell TA, Dry SM, Li Y, Yamamoto N, Hayashi K, Kimura H, Miwa S, Tsuchiya H, Singh SR, Eilber FC, Hoffman RM (2018) Tumor-targeting Salmonella typhimurium A1-R is a highly effective general therapeutic for undifferentiated soft tissue sarcoma patient-derived orthotopic xenograft nude-mouse models. Biochem Biophys Res Commun 497(4):1055–1061

    Article  CAS  Google Scholar 

  15. Kawaguchi K, Igarashi K, Miyake K, Kiyuna T, Miyake M, Singh AS, Chmielowski B, Nelson SD, Russell TA, Dry SM, Li Y, Unno M, Singh SR, Eilber FC, Hoffman RM (2019) Patterns of sensitivity to a panel of drugs are highly individualised for undifferentiated/unclassified soft tissue sarcoma (USTS) in patient-derived orthotopic xenograft (PDOX) nude-mouse models. J Drug Target 27(2):211–216

    Article  CAS  Google Scholar 

  16. Morgan M, El Shaikh MA, Abu-Isa E, Davis MA, Lawrence TS (2008) Radiosensitization by gemcitabine fixed-dose-rate infusion versus bolus injection in a pancreatic cancer model. Transl Oncol 1(1):44–49

    Article  Google Scholar 

  17. Aston WJ, Hope DE, Nowak AK, Robinson BW, Lake RA, Lesterhuis WJ (2017) A systematic investigation of the maximum tolerated dose of cytotoxic chemotherapy with and without supportive care in mice. BMC Cancer 17(1):684

    Article  Google Scholar 

  18. Tampellini M, Filipski E, Liu XH, Lemaigre G, Li XM, Vrignaud P, François E, Bissery MC, Lévi F (1998) Docetaxel chronopharmacology in mice. Cancer Res 58(17):3896–3904

    CAS  PubMed  Google Scholar 

  19. Lowery CD, Blosser W, Dowless M, Knoche S, Stephens J, Li H, Surguladze D, Loizos N, Luffer-Atlas D, Oakley GJ III, Guo Q, Iyer S, Rubin BP, Stancato L (2018) Olaratumab exerts antitumor activity in preclinical models of pediatric bone and soft tissue tumors through inhibition of platelet-derived growth factor receptor α. Clin Cancer Res 24(4):847–857

    Article  CAS  Google Scholar 

  20. Desai VG, Herman EH, Moland CL, Branham WS, Lewis SM, Davis KJ, George NI, Lee T, Kerr S, Fuscoe JC (2013) Development of doxorubicin-induced chronic cardiotoxicity in the B6C3F1 mouse model. Toxicol Appl Pharmacol 266(1):109–121

    Article  CAS  Google Scholar 

  21. Hida AI, Bando K, Sugita A, Maeda T, Ueda N, Matsukage S, Nakanishi M, Kito K, Miyazaki T, Ohtsuki Y, Oshiro Y, Inoue H, Kawaguchi H, Yamashita N, Aogi K, Moriya T (2015) Visual assessment of Ki67 using a 5-grade scale (Eye-5) is easy and practical to classify breast cancer subtypes with high reproducibility. J Clin Pathol 68(5):356–361

    Article  CAS  Google Scholar 

  22. Chawla SP, Papai Z, Mukhametshina G, Sankhala K, Vasylyev L, Fedenko A, Khamly K, Ganjoo K, Nagarkar R, Wieland S, Levitt DJ (2015) First-line aldoxorubicin vs doxorubicin in metastatic or locally advanced unresectable soft-tissuesarcoma: a phase 2b randomized clinical trial. JAMA Oncol 1(9):1272–1280

    Article  Google Scholar 

  23. Gupta S, Gouw L, Wright J, Chawla S, Pitt D, Wade M, Boucher K, Sharma S (2016) Phase II study of amrubicin (SM-5887), a synthetic 9-aminoanthracycline, as first line treatment in patients with metastatic or unresectable softtissue sarcoma: durable response in myxoid liposarcoma with TLS-CHOP translocation. Investig New Drugs 34(2):243–252

    Article  CAS  Google Scholar 

  24. Schöffski P, Chawla S, Maki RG, Italiano A, Gelderblom H, Choy E, Grignani G, Camargo V, Bauer S, Rha SY, Blay JY, Hohenberger P, D’Adamo D, Guo M, Chmielowski B, Le Cesne A, Demetri GD, Patel SR (2016) Eribulin versus dacarbazine in previously treated patients with advanced liposarcoma or leiomyosarcoma: a randomised, open-label, multicentre, phase 3 trial. Lancet 387(10028):1629–1637

    Article  Google Scholar 

  25. Takahashi M, Takahashi S, Araki N, Sugiura H, Ueda T, Yonemoto T, Morioka H, Hiraga H, Hiruma T, Kunisada T, Matsumine A, Shimura M, Kawai A (2017) Efficacy of trabectedin in patients with advanced translocation-related sarcomas: pooled analysis of two phase II studies. Oncologist 22(8):979–988

    Article  CAS  Google Scholar 

  26. Agulnik M, Costa RLB, Milhem M, Rademaker AW, Prunder BC, Daniels D, Rhodes BT, Humphreys C, Abbinanti S, Nye L, Cehic R, Polish A, Vintilescu C, McFarland T, Skubitz K, Robinson S, Okuno S, Van Tine BA (2017) A phase II study of tivozanib in patients with metastatic and nonresectable soft-tissue sarcomas. Ann Oncol 28(1):121–127

    CAS  PubMed  Google Scholar 

  27. Martin-Liberal J, Pérez E, García Del Muro X (2019) Investigational therapies in phase II clinical trials for the treatment of soft tissue sarcoma. Expert Opin Investig Drugs 28(1):39–50

    Article  CAS  Google Scholar 

  28. García Del Muro X, Maurel J, Martínez Trufero J, Lavernia J, López Pousa A, de Las Peñas R, Cubedo R, Berros JP, Casado Herráez A, de Juan A, Martín Broto J (2018) Phase II trial of ifosfamide in combination with the VEGFR inhibitor sorafenib in advanced soft tissue sarcoma: a Spanish Group for Research on Sarcomas (GEIS) study. Investig New Drugs 36:468–475

    Article  Google Scholar 

  29. Dickson MA, D’Adamo DR, Keohan ML, D’Angelo SP, Carvajal RD, Gounder MM, Maki RG, Qin LX, Lefkowitz RA, McKennon OR, Hirst CM, Schwartz GK, Tap WD (2015) Phase II trial of gemcitabine and docetaxel with bevacizumab in soft tissue sarcoma. Sarcoma 2015:532478

    Article  Google Scholar 

  30. Hensley ML, Miller A, O’Malley DM, Mannel RS, Behbakht K, Bakkum-Gamez JN, Michael H (2015) Randomized phase III trial of gemcitabine plus docetaxel plus bevacizumab or placebo as first-line treatment for metastatic uterine leiomyosarcoma: an NRG Oncology/Gynecologic Oncology Group study. J Clin Oncol 33(10):1180–1185

    Article  CAS  Google Scholar 

  31. Vincenzi B, Badalamenti G, Napolitano A, Spalato Ceruso M, Pantano F, Grignani G, Russo A, Santini D, Aglietta M, Tonini G (2017) Olaratumab: PDGFR-α inhibition as a novel tool in the treatment of advanced soft tissue sarcomas. Crit Rev Oncol Hematol 118:1–6

    Article  Google Scholar 

  32. Chiorean EG, Sweeney C, Youssoufian H, Qin A, Dontabhaktuni A, Loizos N, Nippgen J, Amato R (2014) A phase I study of olaratumab, an anti-platelet-derived growth factor receptor alpha (PDGFRα) monoclonal antibody, in patients with advanced solid tumors. Cancer Chemother Pharmacol 73(3):595–604

    Article  CAS  Google Scholar 

  33. Loizos N, Xu Y, Huber J, Liu M, Lu D, Finnerty B, Rolser R, Malikzay A, Persaud A, Corcoran E, Deevi DS, Balderes P, Bassi R, Jimenez X, Joynes CJ, Mangalampalli VR, Steiner P, Tonra JR, Wu Y, Pereira DS, Zhu Z, Ludwig DL, Hicklin DJ, Bohlen P, Witte L, Kussie P (2005) Targeting the platelet-derived growth factor receptor-α with a neutralizing human monoclonal antibody inhibits the growth of tumor xenografts: implications as a potential therapeutic target. Mol Cancer Ther 4(3):369–379

    CAS  PubMed  Google Scholar 

  34. Tobias A, O’brien MP, Agulnik M (2017) Olaratumab for advanced soft tissue sarcoma. Expert Rev Clin Pharmacol 10(7):699–705

    Article  CAS  Google Scholar 

  35. Deevi DS, Lariccia L, Wang S, Joynes C, Steiner P, Bruheim S, Fodstad O, Carrick FE, Tonra JR, Loizos N (2006) Inhibition of human osteosarcoma xenograft growth by anti-platelet derived growth factor receptor alpha antibody, IMC-3G3, alone and in combination with chemotherapy. Cancer Res 66:877–877

    Google Scholar 

  36. Wagner AJ, Kindler H, Gelderblom H, Schöffski P, Bauer S, Hohenberger P, Kopp HG, Lopez-Martin JA, Peeters M, Reichardt P, Qin A, Nippgen J, Ilaria RL, Rutkowski P (2017) A phase II study of a human anti-PDGFRα monoclonal antibody (olaratumab, IMC-3G3) in previously treated patients with metastatic gastrointestinal stromal tumors. Ann Oncol 28(3):541–546

    Article  CAS  Google Scholar 

  37. Gerber DE, Swanson P, Lopez-Chavez A, Wong L, Dowlati A, Pennell NA, Cronier DM, Qin A, Ilaria R Jr, Cosaert J, Shahir A, Baggstrom MQ (2017) Phase II study of olaratumab with paclitaxel/carboplatin (P/C) or P/C alone in previously untreated advanced NSCLC. Lung Cancer 111:108–115

    Article  Google Scholar 

  38. McGuire WP, Penson RT, Gore M, Herraez AC, Peterson P, Shahir A, Ilaria R Jr (2018) Randomized phase II study of the PDGFRα antibody olaratumab plus liposomal doxorubicin versus liposomal doxorubicin alone in patients with platinum-refractory or platinum-resistant advanced ovarian cancer. BMC Cancer 18(1):1292

    Article  CAS  Google Scholar 

  39. Hakenberg OW, Perez-Gracia JL, Castellano D, Demkow T, Ali T, Caffo O, Heidenreich A, Schultze-Seemann W, Sautois B, Pavlik I, Qin A, Novosiadly RD, Shahir A, Ilaria R Jr, Nippgen J (2019) Randomised phase II study of second-line olaratumab with mitoxantrone/prednisone versus mitoxantrone/prednisone alone in metastatic castration-resistant prostate cancer. Eur J Cancer 107:186–195

    Article  CAS  Google Scholar 

  40. Jones RL, Mo G, Baldwin JR, Peterson PM, Ilaria RL Jr, Conti I, Cronier DM, Tap WD (2019) Exposure-response relationship of olaratumab for survival outcomes and safety when combined with doxorubicin in patients with soft tissue sarcoma. Cancer Chemother Pharmacol 83(1):191–199

    Article  CAS  Google Scholar 

  41. Zuluaga-Sanchez S, Hess LM, Wolowacz SE, D’yachkova Y, Hawe E, Vickers AD, Kaye JA, Bertwistle D (2018) Cost-effectiveness of olaratumab in combination with doxorubicin for patients with soft tissue sarcoma in the United States. Sarcoma 2018:6703963

    Article  Google Scholar 

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Acknowledgements

This paper is dedicated to the memory of A. R. Moossa, M.D., Sun Lee, M.D., and Professor Li Jiaxi.

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Authors and Affiliations

  1. AntiCancer, Inc., San Diego, CA, USA

    Takashi Higuchi, Kentaro Miyake, Norihiko Sugisawa, Hiromichi Oshiro, Zhiying Zhang, Sahar Razmjooei & Robert M. Hoffman

  2. Department of Surgery, University of California, San Diego, CA, USA

    Takashi Higuchi, Kentaro Miyake, Norihiko Sugisawa, Hiromichi Oshiro, Zhiying Zhang, Michael Bouvet & Robert M. Hoffman

  3. Department of Orthopedic Surgery, Kanazawa University, Kanazawa, Japan

    Takashi Higuchi, Norio Yamamoto, Katsuhiro Hayashi, Hiroaki Kimura, Shinji Miwa, Kentaro Igarashi & Hiroyuki Tsuchiya

  4. Basic Research Laboratory, National Cancer Institute, Frederick, MD, USA

    Shree Ram Singh

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  1. Takashi Higuchi
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Corresponding authors

Correspondence to Shree Ram Singh, Hiroyuki Tsuchiya or Robert M. Hoffman.

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Conflict of interest

The authors declare that they have no conflict of interest. T.H., K.M., N.S., H.O., Z.Z., S.R., N.Y., K.H., H.K., S.M., K.I., and R.M.H. are or were unsalaried associates of AntiCancer, Inc. AntiCancer, Inc. uses PDOX models for contract research.

Ethical approval

All experiments were performed with an AntiCancer Institutional Animal Care and Use Committee (IACUC)-protocol specifically approved for this study and in accordance with the principals and procedures outlined in the National Institutes of Health Guide for the Care and Use of Animals under Assurance Number A3873-1.

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Written informed consent was obtained from the patient as part of a UCLA Institutional Review Board approved protocol (IRB#10-001857).

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Higuchi, T., Miyake, K., Sugisawa, N. et al. The combination of olaratumab with gemcitabine and docetaxel arrests a chemotherapy-resistant undifferentiated soft-tissue sarcoma in a patient-derived orthotopic xenograft mouse model. Cancer Chemother Pharmacol 83, 1075–1082 (2019). https://doi.org/10.1007/s00280-019-03824-3

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